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cis-Determinants in the cytoplasmic domain of CEACAM1 responsible for its tumor inhibitory function
1Department of Biochemistry, McGill Cancer Centre, McIntyre Medical Sciences Building, McGill University, Montreal, Québec, Canada.
Abstract:
CEACAM1, also known as C-CAM, BGP and CD66a, is a member of the carcinoembryonic antigen (CEA) family which is itself part of the immunoglobulin supergene family. CEACAM1 is involved in intercellular adhesion, signal transduction and tumor cell growth regulation. CEACAM1 is down-regulated in colon and prostate carcinomas, as well as in endometrial, bladder and hepatic tumors, and 30% of breast cancers. We have shown in a mouse colon tumor model that CEACAM1 with a long cytoplasmic domain inhibited the development of tumors whereas a splice variant lacking the cytoplasmic domain did not. In this study, we define the subregions of the long cytoplasmic domain participating in the tumor inhibition phenotype of CEACAM1. We show that a single point mutation of Tyr488, conforming to an Immunoreceptor Tyrosine Inhibition Motif (ITIM), was sufficient to reverse the in vivo tumor cell growth inhibition. Substitution or deletion of residues in the C-terminal region of the CEACAM1 cytoplasmic domain also led to reversal of tumor cell growth inhibition. This result is in agreement with our previous studies demonstrating the C-terminal region of the cytoplasmic domain influences the levels of CEACAM1 Tyr phosphorylation and its association with the protein Tyr phosphatases SHP-1 and SHP-2. Furthermore, removal of the N-terminal domain of CEACAM1, essential for intercellular adhesion, did not impair the tumor inhibitory effect. These results suggest that Tyr phosphorylation or dephosphorylation of the CEACAM1 cytoplasmic domain represents a crucial step in the control of epithelial cell proliferation.
Insights
The CEACAM1 protein
Area of Science:
- Molecular Biology
- Cancer Research
- Cell Biology
Background:
- CEACAM1 is a member of the carcinoembryonic antigen (CEA) family, involved in cell adhesion and tumor growth regulation.
- CEACAM1 is frequently downregulated in various cancers, including colon, prostate, and breast carcinomas.
- A long cytoplasmic domain of CEACAM1 inhibits tumor development, while a variant lacking it does not.
Purpose of the Study:
- To identify specific subregions within the CEACAM1 cytoplasmic domain responsible for tumor inhibition.
- To investigate the role of tyrosine phosphorylation and specific motifs in CEACAM1's tumor suppressive function.
Main Methods:
- Site-directed mutagenesis to alter specific residues within the CEACAM1 cytoplasmic domain, including the ITIM motif at Tyr488.
- Analysis of tumor growth in a mouse colon tumor model with varying CEACAM1 constructs.
- Assessment of CEACAM1's association with tyrosine phosphatases SHP-1 and SHP-2.
Main Results:
- A single point mutation at Tyr488 (ITIM) reversed the tumor growth inhibition mediated by CEACAM1.
- Alterations in the C-terminal region of the cytoplasmic domain also abolished the tumor inhibitory effect.
- The N-terminal domain, crucial for cell adhesion, was not essential for CEACAM1's tumor suppressive function.
Conclusions:
- Tyrosine phosphorylation/dephosphorylation of the CEACAM1 cytoplasmic domain is critical for regulating epithelial cell proliferation.
- Specific residues and motifs within the CEACAM1 cytoplasmic domain, particularly Tyr488 and the C-terminal region, are key to its tumor suppressor activity.